There currently is no effective treatment for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). In all of these disorders, proteins in which mutations induce a toxic gain of function are thought to play a causal or pathogenic role. This newly acquired toxic function often is either multifactorial or incompletely understood. Reducing the expression of the mutant protein is one therapeutic strategy of which the success is independent of the understanding of the pathogenic action of the protein.
ALS is an adult-onset neurodegenerative disease that affects the upper and lower motoneurons (MNs) in the cerebral cortex, brain stem, and spinal cord. It results in progressive MN loss, muscle paralysis and atrophy leading to death within a few years. Most ALS patients are thought to have a sporadic form of the disease, but in about 10% of patients, ALS is inherited or familial (FALS). In about 20% of patients with FALS, the disease is caused by mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) (Rosen et al., 1993). Other causes are mutations in TARP, FUS/TLS, VCP and C9ORF72. Overexpression of mutated human SOD1 in transgenic animals, both mice (Gurney et al., 1994) and rats (Nagai et al., 2001), results in the development of a lethal motor neuron disease. More than 150 distinct SOD1 point mutations have been described including cases in which enzymatic activity is increased, decreased or non-altered (cf. the ALS Online genetics Database on the World Wide Web at alsod.iop.kcl.ac.uk/). Therefore, a toxic gain of function is generally accepted to underlie neuronal toxicity of mutant SOD1. Mutant SOD1 has been found to be misfolded,4-5 and it is hypothesized that this toxicity is related to the formation of high-molecular-weight complexes and, in a final stage, the formation of aggregates,6-7 a hallmark of many neurodegenerative diseases (Zhang and Zhu, 2006; Ross and Poirier, 2004).
Furthermore, wild-type SOD1 has been suggested to play a role in the pathogenesis of sporadic ALS.8 It has been proposed that in sporadic ALS, wild-type SOD1 undergoes secondary modifications (e.g., through oxidation or demetalation), misfolds and is toxic to motor neurons in a very similar manner to what is seen with mutant SOD1.9 Using a conformation-specific antibody that recognizes the misfolded species selectively, pathogenic SOD1 has been found in motor neurons of at least a part of sporadic ALS patients.1 Most interestingly, the toxic effect of astrocytes from sporadic ALS patients (thus not harboring SOD1 mutations) on motor neurons is dependent on the presence of SOD1.2 
Therefore, reducing the levels of the pathogenic SOD1 is an interesting strategy to treat patients with mutant SOD1-associated familial ALS, as well as patients with sporadic ALS. To achieve this, anti-sense oligonucleotide, siRNA-based and immunological approaches have been developed. For the latter, both active and passive immunization is under investigation. However, approaches using siRNA and conventional antibodies come with significant problems (e.g., half-life, distribution in the CNS, uptake by neurons, etc.), and none of these approaches has thus far led to a therapy for ALS.
Accordingly, there is a pressing need for new therapies for ALS, particularly therapies that address the above-mentioned problems.